We are using molecular genetic approaches in humans and knock-in mice, with precisely targeted gene mutations, to understand the basis of inherited human neurodegenerative diseases. Two major interests, where we have identified the underlying gene defects and have made genetically accurate mouse and neuronal cell models, are Huntington’s disease (HD) and Neuronal Ceroid Lipofuscinosis (NCLs).

HD is a dominant, typically adult onset disorder that features the loss of striatal neurons. The HD gene defect expands, into the disease-causing range, a functional CAG triplet repeat polymorphism. This repeat encodes a polyglutamine tract that quantitatively alters the structure and enhances the function of huntingtin, an ancient 350 kDa alpha-helical HEAT domain protein that serves to organize members of macromolecular complexes.

The NCLs are recessive disorders of childhood that feature the loss of retinal and CNS neurons, with the timing of onset of symptoms determined by the CLN gene involved and the particular loss of function mutation. The CLN genes encode different small transmembrane proteins of, for example, the endoplasmic reticulum or the lysosomal system, involved in autophagy.

Our studies favor global unbiased strategies for investigating the normal functions of the disease genes and the immediate effects of the disease-causing mutations, such as genetic screens for modifying loci, whole genome RNA expression, proteomics and metabolomic analyses, but also extend to testing hypotheses using biochemical approaches, for example protein purification and the generation of activity assays.